Inter-Enzyme Crosstalk in the Cytochrome P450 Ensemble: Implications for the Effects of Alcohol on Drug Metabolism and Alcohol-Drug Interactions

细胞色素 P450 整体中的酶间串扰：酒精对药物代谢和酒精-药物相互作用影响的影响

• 批准号: 10704053
• 负责人: Dmitri R Davydov
• 金额: $ 50.08万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-13 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704053
• 关键词: AODR mortality; Adverse drug effect; Adverse effects; Affect; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohol-Induced Disorders; Alcohols; Biological Assay; CYP1A2 gene; CYP2C19 gene; CYP2C9 gene; CYP2D6 gene; CYP2E1 gene; CYP3A4 gene; Chemicals; Chronic; Clinical; Cocaine; Collection; Complex; Cytochrome P450; Diazepam; Drug Interactions; Drug Kinetics; Drug Metabolism Induction; Drug Prescriptions; Drug usage; Eicosanoids; Endoplasmic Reticulum; Enzyme Induction; Enzymes; Foundations; Genotype; Goals; Health; Hepatocyte; Human; Hypertension; Individual; Knowledge; Knowledge acquisition; Life; Liver; Liver Microsomes; Mass Spectrum Analysis; Mediating; Medical; Membrane; Metabolic; Metabolism; Minor; Opioid; Pathogenesis; Pharmaceutical Preparations; Phenytoin; Physiological; Play; Preparation; Prevention; Property; Proteins; Proteomics; Public Health; Recording of previous events; Regulation; Research; Role; Route; Series; Signal Pathway; Signal Transduction; Substrate Specificity; System; Systems Integration; Therapeutic; Tissues; Tolbutamide; Tretinoin; Warfarin; alcohol abuse therapy; alcohol effect; alcohol exposure; alcohol use disorder; carcinogenesis; crosslink; drug metabolism; drug of abuse; high throughput screening; insight; intermolecular interaction; interspecies communication; pharmacokinetics and pharmacodynamics; pharmacologic; protein expression; protein protein interaction

The effect of alcohol consumption on drug metabolism and interactions of alcohol with drugs constitute a significant health problem. The mechanisms of these effects are tightly related to the influence of alcohol on drug- metabolizing system, and on cytochrome P450 ensemble in particular. Functional versatility of the cytochrome P450 system is achieved through the presence of over a dozen of P450 species differing in their substrate specificity. The composition of this ensemble is known to be largely affected by alcohol consumption. It is generally presumed that the integral properties of this ensemble represent a simple aggregate of the properties of the constituting P450 enzymes. Although this premise remains to be a foundation of rational analysis of the routes of drug metabolism, its validity became essentially compromised. The body of evidence of system-wide integration in the properties of the P450 ensemble continues to grow. The current project is prompted by recognition of a far-reaching physiological significance and pharmacological importance of inter-species crosstalk in the P450 ensemble and its thorough relevance to the effects of alcohol on drug metabolism and P450- dependent cellular signaling. Our central hypothesis is that the results of the alcohol-induced changes in the composition of the cytochrome P450 pool are not limited to direct consequences of the activity of the alcohol-induced enzymes. They also involve alterations of the metabolism of a broad range of exogenous and endogenous substrates of various P450 enzymes due to their interactions with alcohol-inducible P450 species. These indirect effects are deeply involved in clinically-important cases of alcohol interactions with drugs and alcohol-induced alteration of cellular signaling through eicosanoids, retinoic acid and other P450-dependent messengers. This proposal is aimed to explore the alcohol-induced changes in P450 expression and their effects of on the network of protein-protein interaction in the ER membranes and, consequently, on the system-wide properties of the P450 ensemble. Our long-term goal is to obtain a complete picture of functional interactions between human cytochromes P450, and the alcohol-inducible P450 species in particular, and characterize their role in dictating the integral properties of the drug-metabolizing ensemble and their changes by alcohol consumption. Specific Aims of the project are: (1) To refine our knowledge on alcohol-induced changes in the composition of the cytochrome P450 ensemble in liver cells; (2) To identify the principal intermolecular interactions of alcohol- induced P450 species in HLM; (3) To identify the major functional interactions of alcohol-inducible P450 enzymes with other P450 species and explore their effect on the metabolism of drugs and endogenous substrates by the P450 ensemble. Fulfilling these aims will allow in-depth characterization of alcohol-induced changes in drug-metabolism and P450-dependent cellular signaling and understand their role in deleterious alcohol-drug interactions and other adverse effects of alcohol consumption.

饮酒对药物代谢和酒精与药物相互作用的影响构成了 重大健康问题。这些作用的机制与酒精对药物的影响密切相关 - 代谢系统，尤其是在细胞色素P450集合上。细胞色素的功能多功能性 P450系统是通过存在超过十二种P450物种来实现的，其底物不同 特异性。已知该合奏的组成在很大程度上受到饮酒的影响。这是 通常认为该集合的整体属性代表了属性的简单汇总 构成P450酶的酶。尽管这个前提仍然是对 药物代谢的途径，其有效性基本上受到了损害。整个系统范围的证据 P450合奏性能中的集成继续增长。当前项目是由 认识到深远的生理意义和串扰种间的药理意义 在P450合奏中，与酒精对药物代谢和P450-的影响有关 依赖的细胞信号传导。 我们的中心假设是，酒精诱导的细胞色素成分变化的结果 P450池不仅限于酒精诱导酶活性的直接后果。他们也是 涉及各种P450的广泛的外源和内源性底物的代谢改变 酶由于其与酒精诱导的P450种的相互作用而引起的。这些间接效果深深涉及 在临床上至关重要的情况下，酒精与药物相互作用和酒精诱导的细胞改变 通过类花生酸，视黄酸和其他依赖P450依赖的使者信号传导。 该提案旨在探讨酒精引起的P450表达变化及其对 ER膜中蛋白质 - 蛋白质相互作用的网络，因此，在全系统范围内 P450合奏。我们的长期目标是获得有关功能相互作用的完整图片 人类细胞色素P450尤其是酒精诱导的P450物种，并表征了它们在 决定药物代谢合奏的整体特性及其通过饮酒而变化。 该项目的具体目的是：（1）完善我们对酒精诱导的变化的了解的知识 肝细胞中的细胞色素P450集合； （2）确定酒精的主要分子间相互作用 HLM诱导P450种； （3）确定酒精诱导P450的主要功能相互作用 酶与其他P450种，并探索它们对药物和内源性底物代谢的影响 由P450合奏。实现这些目标将允许对酒精引起的变化进行深入表征 药物代谢和p450依赖性的细胞信号传导，并了解它们在有害酒精毒品中的作用 饮酒的相互作用和其他不利影响。

项目成果

High-Throughput Assay of Cytochrome P450-Dependent Drug Demethylation Reactions and Its Use to Re-Evaluate the Pathways of Ketamine Metabolism.

• DOI: 10.3390/biology12081055
• 发表时间: 2023-07-27
• 期刊: Biology
• 影响因子: 4.2